Isotope Separation System with Velocity Filter

This application claims the benefit of priority to U.S. Provisional Application No. 63/640,156 titled “Systems and Methods for Lu-177 Isotopic Production and Separation,” filed Apr. 29, 2024, which is hereby incorporated by reference in its entirety for all purposes.

Owing to its favorable decay characteristics, Lu-177 is an attractive radionuclide for a variety of medical diagnostic and therapeutic applications. Lu-177 can be produced by two different neutron routes, the direct route [Lu(n,γ)Lu] using natural or enriched Lu-176, and the indirect route [Yb(n,γ)Yb→Lu+β] using highly enriched Yb-176.

Each route produces a product of distinctly different specific activity and radionuclide composition. Of these two options, the indirect route has seen significant modern industrial investment due to the inherent capability of producing a high specific activity non-carrier added product when using highly enriched Yb-176 and coupled with an appropriate radiochemical separation process. Paradoxically, these two features of the indirect route (use of highly enriched Yb-176 and radiochemical separation) are the primary impediments to wide-scale high volume production using this method. In the first case, obtaining highly enriched Yb-176 is difficult due to its limited manufacture and availability, which has only been complicated by the increasing market demand for Lu-177. Further, due to the nuclear properties of Yb-168 and Yb-174, the isotopic purity of the starting material must be very high for an enriched stable isotope and is generally required to be greater than 99.7% Yb-176 to prevent the production of radio and chemical interferents in the final product. These concerns further complicate the manufacture, handling, and reclamation of highly enriched Yb-176 and significantly increase its associated costs. In the second case, the chemical properties of lutetium and ytterbium are different enough to make chemical separation possible using a few potential proprietary processes, but similar enough to make chemical separation very difficult as production scale increases. The final point to be made regarding the indirect route is that the meager neutron capture cross-section (2.6 b) of Yb-176 limits the ability of this process to produce industrially useful quantities of Lu-177 without access to high flux nuclear research reactors and large mass inventories of the difficult to obtain highly enriched Yb-176 as well as significant capital investment for multiple parallel radiochemical processing and Yb-176 reclamation trains.

In opposition to the indirect route, the production of Lu-177 by the direct [Lu(n,γ)Lu] reaction pathway by thermal neutron capture has a very high production yield characterized by the large neutron capture cross-section of Lu-176 (2020 b), allowing the process to produce large quantities without the need for access to high flux nuclear research reactors or highly enriched starting material (and will in fact out-perform the indirect method using only natural, unenriched lutetium (2.6% Lu-176). Further, the direct route can be easily scaled to high volume manufacturing without concern for radio or chemical interferents, or the need for proprietary radiochemical separation processes or equipment. The only tangible drawback of the direct route is the limited technology available to isotopically purify the final product in order to produce a high-specific activity non-carrier added product.

Isotope separation is a field of technology that involves isolating specific isotopes of elements from mixtures containing multiple isotopes. This process has applications in various industries, including nuclear energy, medical diagnostics and treatments, and scientific research. Isotope separation techniques typically exploit small differences in the physical or chemical properties of isotopes to achieve separation.

Several methods have been developed for isotope separation, including gaseous diffusion, centrifugation, electromagnetic separation, and laser isotope separation. These techniques vary in their efficiency, scalability, and suitability for different elements and applications. Advances in areas such as ion optics, high-vacuum systems, and precision control of electromagnetic fields have enabled improvements in the design and performance of isotope separation systems over time.

Various embodiments include equipment, methods, and techniques necessary to produce a high-specific activity of a radionuclide, such as but not limited to Lu-177, for use in nuclear medicine products. Some embodiments may utilize the direct [Lu(n,γ)Lu] reaction pathway, thereby overcoming supply and yield issues commonly encountered with the indirect [Yb(n,γ)Yb→Lu+β] route to produce high-specific activity, non-carrier added Lu-177. To support the production of radiopharmaceutical quantities of Lu-177 using the direct reaction, various embodiments provide systems, equipment, and methods for separating Lu-177 from the Lu-176 target material to produce kilocurie quantities of high-specific activity Lu-177.

Various embodiments will be described in detail with reference to the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts. References made to particular examples and implementations are for illustrative purposes and are not intended to limit the scope of the claims.

Various embodiments provide systems and methods for isotope separation using a velocity filter for use in radioisotope production. Various embodiments include an isotope separation system comprising an ion source assembly, an injector assembly, a separator assembly with a velocity filter, a drift path, a collimator, and an isotope collector module. The velocity filter incorporates electrodes with curved portions to maintain a constant ratio of electric to magnetic field strengths, enabling precise separation of target isotopes and enhanced mass resolution by the system.

The isotope separation system can be configured to isolate specific radioisotopes, such as Lu-177, with high efficiency and purity. The modular design allows for the collection of separated isotopes without disrupting the vacuum environment of the main system, enabling continuous operation and improved productivity.

Various embodiments provide improvements to radioisotope production technologies by enabling high-resolution separation of isotopes with similar masses, increasing the specific activity of the collected product, and allowing for controlled collection rates to meet precise production requirements.

While chemical elements can be purified through chemical processes, isotopes of the same element have nearly identical chemical properties, making chemical separation impractical for all elements except hydrogen. The first technology able to separate, isolate, and/or concentrate isotopes was originally conceived at the University of California, Berkeley by Ernest O. Lawrence. At Oak Ridge National Laboratory, under the auspices of the Manhattan project, the first electromagnetic isotope separators based on his concept were developed to produce the majority of the highly enriched uranium used in the first atomic bombs. These isotope separation devices were called calutrons and operated continuously between 1940 and 1945 to produce highly enriched uranium, before being transitioned to produce other enriched stable isotopes for research purposes. Multiple versions of the calutron were designed and operated in the intervening years until finally ceasing operation in 1998. Countries such as Russia and China continue to operate isotope separators based on the Calutron design to produce enriched stable isotopes for almost every industry.

Current isotope separation systems often struggle to achieve high mass resolution and purity when separating isotopes with very similar masses, such as Lu-177 from other lutetium isotopes. Existing electromagnetic separators typically have limited throughput or require large, complex installations that are impractical for many applications. Additionally, conventional systems often lack the ability to precisely control the rate of isotope collection to match specific production requirements. Therefore, there is an unmet need for an isotope separation system that can achieve high mass resolution and purity in a compact design, while allowing for controlled collection rates to produce radioisotopes like Lu-177 with high specific activity for medical and research applications.

Each reactor target may contain no more than 100 mg of high elemental purity lutetium metal, either in natural, low-enriched or highly-enriched abundances of Lu-176. Given the high density of lutetium metal (9.841 g/cm), 100 mg is roughly equivalent to the size of a single 0.7 mm mechanical pencil lead, irradiation targets are expected to be pre-deposited onto a substrate material. Reactor grade zirconium has been determined as the best option due to its low neutron activation, chemical inertness, high melting point, and low vapor pressures as compared to lutetium.

Multiple concepts for the physical design of the reactor target are possible, such as a disk target or a filament target.

A 25 mm disk target may be a 100 μm-thick zirconium disk, 25 mm in diameter. The disk could be plated by either evaporative or sputter deposition of lutetium to a thickness of 20 μm. The 25 mm disk may emulate a common reactor target shape normally used for the production of molybdenum-99 from high-purity molybdenum-98, in which multiple target disks are stacked up to 50 mm for a single irradiation. This target form may be used with a Nier-Bernas style ion source, in which the disk is inserted into a position where it can act as the anti-cathode and be indirectly heated independently of the cathode.

The filament target may be envisioned as a wound 1 mm wire filament coil, 6 mm OD by 40 mm long, and having a pitch of 5 mm per revolution. The lutetium may be plated by either evaporative or sputter deposition to a thickness of 20 μm and fully covering the coils within 6 mm on either side of the coil center, and separately encapsulated in an 8 mm OD quartz tube for shipping and irradiation. This target form may be used with a Neir-Bernas style ion source, in which the coil is inserted along the central axis of the cylindrical arc chamber and directly heated similarly to a thermionic filament.

Other potential target configurations include a needle, such as a needle of Zr coated with Lu metal by plating, or evaporative or sputter deposition, a hollow needle having an interior volume of lutetium chloride formed by drawing a LuClsolution into the needle followed by desiccation, or a wire mesh of Zr on which Lu metal is plated.

Regardless of configuration, the target will be separately encapsulated and hermetically sealed within an ampoule containing an inert gas atmosphere. The ampoule can be any of the low-activating, high-purity transition metals, including titanium, zirconium, aluminum, or quartz tubing as specifically directed by the requirements of the irradiator. The encapsulation must be leak checked after sealing to ensure a fully hermetic environment prior to being shipped to the irradiator.

Once targets have been prepared and encapsulated, they will be shipped directly to the location of the irradiation services provider where the target and its encapsulation will be removed from packaging and inserted into a nuclear reactor having an average thermal neutron flux no less than 3×10n/cm-s for a period of time between 5 and 7 days. Irradiations at conditions less than those specified can be utilized for testing and validation purposes, but will not produce a sufficient activity of Lu-177 feasible for collection in a reasonable amount of time.

Following irradiation, it may be necessary to store targets on-site for short periods to allow the decay of short-lived radioactive by-products, but targets are expected to contain between 2500 to 3200 Ci of Lu-177 by the time they are received for post-irradiation separation and processing. Once the irradiated capsule is returned and prepared for isotopic separation, the target is removed from the encapsulation.

Prioritizing the mass resolution may be an important aspect of the isotope separation system design because that may enable production of a Lu-177 product of such high-specific activity that it exceeds or at a minimum equals the therapeutic performance of Lu-177 products available using other isotope isolation methods.

Determining the design parameters of the separation process begins with determining the effective mass resolution of the system. While the final system design needs to account for multiple coupled physics phenomena to achieve the specified mass resolution, the specific value of the mass resolution required can be determined based solely on an analysis of the estimated composition of the beam at the entrance of the separator assembly. A complicating factor to this analysis specific to this particular application is the changes anticipated in the beam composition over time due to the decay of Lu-177.

The mass resolution of the system is specifically coupled to the achievable specific activity of the final product. For example, for a system isolating Lu-177, a minimum specification for a non-carrier added product may be greater than 3000 GBq per mg. The theoretical maximum specific activity of Lu-177 is 4108 GBq per mg.

The physical separation between the ion beam peaks in the system required to achieve the appropriate mass resolution at the mass resolving aperture is directly coupled to both the beam width at the beam defining aperture, as well as the mass resolution of the system. In fact, the ratio of the beam width to the mass peak separation distance is equal to the ratio of the mass peak width to the mass peak separation, which together are defined by the mass resolution of the separator.

Determination of the required mass resolution can be performed by analysis based solely on the beam composition, such as the ratio of the atom densities for Lu-175, Lu-176, and Lu-177, as well as other element species within this mass range. In theory, the higher the atom ratio of the product species Lu-177 to the total Lu isotope inventory, the lower the mass resolution of the system that is required to achieve the goal for specific activity of the product.

A mass resolution of 500 or greater results in nearly complete separation of the mass species and will allow collection of the Lu-177 product at both high specific activity and the fully rated mass throughput.

The mass throughput is effectively a metric for how long it takes to process a single target and deliver a single product batch to customers. This aspect heavily impacts the volume of production for a single target and a single machine. Optimizing the mass throughput of the system may be necessary for achieving high-volume production but is most likely to be extraneous when considering the capabilities of the direct [Lu(n,γ)Lu] production pathway, but is still considered a secondary priority as significant importance is assigned within the industry for consistent, on-time delivery of product due to the short effective shelf-life of Lu-177.

From a process perspective, the mass throughput of the system may be defined by how many curies of Lu-177 activity are produced per batch or period (e.g., Ci/h, Ci/d, Ci/batch, etc.). From the system perspective, the mass throughput is more easily defined and measured by the achievable beam current through the separator assembly during operation (e.g., micro-Amperes (μA), milli-Amperes (mA).

Based on experience, a reasonable performance envelope for mass throughput has been determined to be between 100 μA and 1 mA. The lower value was selected to be a reasonably achievable performance value for ion beam devices of a similar size and type as various embodiments, while the upper value was determined by a rough estimation of the theoretical limits for a device of this type.

Analysis of the separation process at both ends of the performance envelope has been performed to develop a foundation for the expected production volume, and has shown that even at the lower performance value of 100 mA, the system will likely have a significant production volume capability as compared to other manufacturing methods for Lu-177.

At the lower performance value of 100 μA it is anticipated that a single 100 mg target will be fully processed within approximately 6 days, which means that only 1 target per week per machine would need to be irradiated and shipped per week, which is a good match when assuming that an irradiation period is anticipated to be between 5 and 7 days. Designing the system to allow multiple batch extractions during target processing, a single target would be capable of producing 1 product batch per day of operation for a total of 6 product batches per target-machine-week. Each of these product batches would be of a total activity between 200 and 350 Ci assuming an initial target activity of 3200 Ci. When compared against DOT shipping limits for Type A containers, anticipated customer use, and purification process design limits this operating approach is an even more convenient match for the overall process and significantly reduces technical risk. Further, a large amount of flexibility exists within the process to overcome activity and process efficiency limitations, even at the lowest performance value, which far exceeds the capabilities of competing processes based on the indirect [Yb(n,γ)Yb→Lu+β] production pathway.

The process efficiency of the system determines how much of the Lu-177 created during the irradiation process is collected and concentrated into high-specific activity, non-carrier-added Lu-177 product. The process efficiency itself is a bulk metric accounting for material losses at multiple points within the system. Based on the physical operations taking place during separation, the process efficiency can be broken down into several component loss mechanisms, each of which can be addressed independently to impact the overall process efficiency.

The utilization efficiency is specific to the vaporization process occurring within the source module and is primarily impacted by the formation of molecular lutetium complexes, the largest example being oxidation of the lutetium metal to form LuO. The ion source vaporization process may use lutetium in metal form. Formation of oxides during handling processes will cause those molecules to be un-vaporizable and become sequestered within the ion source for the duration of the process. Other contributors to this loss mechanism include conversion of metal through other chemical reactions, the formation of solid solutions with the target substrate, and even re-deposition of the lutetium vapor outside of the ionization region of the ion source. Loss by these mechanisms may be controlled by ensuring hermetic sealing during encapsulation and handling within inert environments. A utilization efficiency of ˜95% is expected to be achievable based on prior experience.

The ionization efficiency is a measure of the ion source's ability to ionize the lutetium vapor into the +1 charge state. It is anticipated that some minor fraction of lutetium atoms will not be fully ionized before passing through the ionizing region of the ion source, will be neutralized after ionization, and/or will be ionized into higher charge states. This loss mechanism is likely to be the most dominant, and significant design effort may be required to achieve an efficiency of greater than ˜50% without operational experience that includes detailed measurement and design refinement.

The transport efficiency is a metric for ion losses during transport through the machine. The performance of the separator assembly and its achievable mass resolution are sensitive to the beam emittance during transport, which itself is sensitive to the mass throughput of the system.

The collection efficiency is related to the behavior of the collection module of the system. During the collection process, some ions of lutetium will be effectively lost due to several mechanisms, including re-emission and implantation, as well as the effectiveness of the chemical purification process to extract the deposited lutetium from the collection surface.

As a radioisotope, the Lu-177 will be decaying continuously once removed from the reactor, which is characterized by its half-life of 6.6443 days. In other words, 6.6443 days after the target has been removed from the reactor, it will contain only half of its original activity. This will cause the ratio of Lu-177 to Hf-177 (its decay product) to be constantly decreasing. Mitigating this loss mechanism is only possible by increasing the mass throughput of the system, which, for reasons stated previously, impacts other aspects of the overall process effectiveness. Nevertheless, the volume capability of the direct [Lu(n,γ)Lu] production route allows for significant capacity assuming the overall processing period is less than one full half-life of Lu-177.

A post-separation radio-chemical purification and polishing process may be used to ensure that the radiochemical solutions extracted from the product and raffinate collectors meet the requirements of the downstream processes for both final product specification and reclaimed enriched target material.

illustrates major components of an isotope separation systemaccording to various embodiments. The main isotope separation systemincludes components-configured to perform six distinct functions to match the purification and throughput targets. These functions include vaporization of the irradiated element (e.g., Lu), ionization of atoms of the element, emission and acceleration of element ions, transport of the ions through the system, isotopic separation, and collection. These functions may be accomplished in an ion source assembly, an injector assembly, a velocity separator assembly, a drift path, and an isotope collector assembly. Additionally, the isotope separation systemincludes supporting subsystems-providing vacuum and gas management, cooling, power, and overall system control.

The ion source assemblymay be configured to generate ions of a +1 state from a source material, such as lutetium. The ion source assemblymay include a source ovenand a cathode assembly. A charge delivery caskmay be positioned to provide source material to the ion source assembly.

The injector assemblymay be positioned to receive ions from the ion source assembly. In some embodiments, the injector assemblymay accelerate and focus the received ions into a beam.

The velocity separator assemblymay be positioned to receive ions from the injector assembly. In some embodiments, the velocity separator assemblymay comprise a velocity filter with a magnet assembly and two electrodes. The velocity filter may be configured to separate ions based on their velocities as described herein.

The drift pathmay extend from the velocity separator assembly. In some embodiments, the drift pathmay allow separated ion beams to diverge.

The isotope collector assemblymay be positioned at the end of the drift path. In some embodiments, the isotope collector assemblymay include a first removable collection surface to receive the first target isotope ions.

The isotope separation systemmay also include an isotope removal cask. In some embodiments, the isotope removal caskmay be used for removing collected material from the isotope collector assembly.

illustrates one embodiment configuration that may be implemented. As shown in, the isotope separation systemmay include multiple access points for power, control, and instrumentation connections. These may include power and control lead access, power and control lead access, instrument lead access, and instrument lead access. An instrumentation access portmay also be provided.

The isotope separation systemmay incorporate several supporting subsystems. An instrument & control systemmay manage operational parameters of the system. A vacuum and gas systemmay maintain appropriate pressure conditions within the system. The vacuum and gas systemmay include vacuum turbinesand, as well as vacuum chamber isolation gate valvesand.

A power distribution systemmay provide electrical power to the various assemblies and components. A cooling water systemmay provide temperature control for components of the isotope separation system.

In some embodiments, the isotope separation systemmay include a vacuum system configured to maintain vacuum conditions during operation. The vacuum system may maintain vacuum conditions in the ion source assembly, injector assembly, separator assembly, drift path, and isotope collector assembly.